Home LiteratureArticle Details
PMID: 26238514 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Mutations in ARID2 are associated with intellectual disabilities.

Neurogenetics ·Vol. 16 ·No. 4 ·2015-10-00 ·Pages 307-14

Shang L, Cho MT, Retterer K, Folk L, Humberson J, Rohena L, Sidhu A, Saliganan S, Iglesias A, Vitazka P, Juusola J, O'Donnell-Luria AH, Shen Y, Chung WK

Abstract

The etiology of intellectual disabilities (ID) remains unknown for the majority of patients. Due to reduced reproductive fitness in many individuals with ID, de novo mutations account for a significant portion of severe ID. The ATP-dependent SWI/SNF chromatin modifier has been linked with neurodevelopmental disorders including ID and autism. ARID2 is an intrinsic component of polybromo-associated BAF (PBAF), the SWI/SNF subcomplex. In this study, we used clinical whole exome sequencing (WES) in proband-parent-trios to identify the etiology of ID. We identified four independent, novel, loss of function variants in ARID2 gene in four patients, three of which were confirmed to be de novo. The patients all have ID and share other clinical characteristics including attention deficit hyperactivity disorder, short stature, dysmorphic facial features, and Wormian bones. All four novel variants are predicted to lead to a premature termination with the loss of the two conservative zinc finger motifs. This is the first report of mutations in ARID2 associated with developmental delay and ID.

Keywords
ARID2 De novo mutations Intellectual disabilities SWI/SNF chromatin modifier Whole exome sequencing
MeSH Terms
Adolescent Child Developmental Disabilities/genetics Exome Female Humans Intellectual Disability/genetics Male Mutation Transcription Factors/genetics
Chemicals
ARID2 protein, human Transcription Factors
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Shang Linshan
Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.
Cho Megan T
GeneDx, Gaithersburg, MD, USA.
Retterer Kyle
GeneDx, Gaithersburg, MD, USA.
Folk Leandra
GeneDx, Gaithersburg, MD, USA.
Humberson Jennifer
Department of Pediatrics, Division of Genetics and Metabolism, University of Virginia, Charlottesville, VA, USA.
Rohena Luis
Department of Pediatrics, Division of Genetics, San Antonio Military Medical Center, San Antonio, TX, USA.
Sidhu Alpa
Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA.
Saliganan Sheila
Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA.
Iglesias Alejandro
Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.
Vitazka Patrik
GeneDx, Gaithersburg, MD, USA.
Juusola Jane
GeneDx, Gaithersburg, MD, USA.
O'Donnell-Luria Anne H
Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. | Broad Institute of MIT and Harvard, Cambridge, MA, USA. | Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Shen Yufeng
Department of System Biology and Biomedical Informatics, Columbia University Medical Center, New York, NY, 10032, USA.
Chung Wendy K
Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA. wkc15@columbia.edu. | Department of Medicine, Columbia University Medical Center, New York, NY, USA. wkc15@columbia.edu.
References (52)
52 references, click to expand
  1. Intellectual disability and autism spectrum disorders: causal genes and molecular mechanisms.
    Neurosci Biobehav Rev. 2014 Oct;46 Pt 2:161-74 PMID: 24709068
  2. ARID proteins: a diverse family of DNA binding proteins implicated in the control of cell growth, differentiation, and development.
    Cell Growth Differ. 2002 Mar;13(3):95-106 PMID: 11959810
  3. Integrated analysis of whole genome and transcriptome sequencing reveals diverse transcriptomic aberrations driven by somatic genomic changes in liver cancers.
    PLoS One. 2014 Dec 19;9(12):e114263 PMID: 25526364
  4. The human SWI/SNF-B chromatin-remodeling complex is related to yeast rsc and localizes at kinetochores of mitotic chromosomes.
    Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13015-20 PMID: 11078522
  5. Two related ARID family proteins are alternative subunits of human SWI/SNF complexes.
    Biochem J. 2004 Oct 15;383(Pt 2):319-25 PMID: 15170388
  6. ClinVar: public archive of relationships among sequence variation and human phenotype.
    Nucleic Acids Res. 2014 Jan;42(Database issue):D980-5 PMID: 24234437
  7. An integrated map of genetic variation from 1,092 human genomes.
    Nature. 2012 Nov 1;491(7422):56-65 PMID: 23128226
  8. An essential switch in subunit composition of a chromatin remodeling complex during neural development.
    Neuron. 2007 Jul 19;55(2):201-15 PMID: 17640523
  9. A specificity and targeting subunit of a human SWI/SNF family-related chromatin-remodeling complex.
    Mol Cell Biol. 2000 Dec;20(23):8879-88 PMID: 11073988
  10. DNA-binding properties of ARID family proteins.
    Nucleic Acids Res. 2005 Jan 07;33(1):66-80 PMID: 15640446
  11. Comprehensive single cell-resolution analysis of the role of chromatin regulators in early C. elegans embryogenesis.
    Dev Biol. 2015 Feb 15;398(2):153-62 PMID: 25446273
  12. SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution.
    Hum Mol Genet. 2010 Jul 15;19(14):2841-57 PMID: 20457675
  13. The contribution of de novo coding mutations to autism spectrum disorder.
    Nature. 2014 Nov 13;515(7526):216-21 PMID: 25363768
  14. CHARGE syndrome: an update.
    Eur J Hum Genet. 2007 Apr;15(4):389-99 PMID: 17299439
  15. CHD7 cooperates with PBAF to control multipotent neural crest formation.
    Nature. 2010 Feb 18;463(7283):958-62 PMID: 20130577
  16. SWI/SNF factors required for cellular resistance to DNA damage include ARID1A and ARID1B and show interdependent protein stability.
    Cancer Res. 2014 May 1;74(9):2465-75 PMID: 24788099
  17. Zipzap/p200 is a novel zinc finger protein contributing to cardiac gene regulation.
    Biochem Biophys Res Commun. 2006 Aug 4;346(3):794-801 PMID: 16782067
  18. Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A.
    Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75 PMID: 25168959
  19. SRF regulates Bcl-2 expression and promotes cell survival during murine embryonic development.
    EMBO J. 2004 Apr 21;23(8):1834-44 PMID: 15057274
  20. Genetic and epigenetic networks in intellectual disabilities.
    Annu Rev Genet. 2011;45:81-104 PMID: 21910631
  21. Molecular findings among patients referred for clinical whole-exome sequencing.
    JAMA. 2014 Nov 12;312(18):1870-9 PMID: 25326635
  22. Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin.
    Mol Cell. 2014 Sep 4;55(5):723-32 PMID: 25066234
  23. A de novo paradigm for mental retardation.
    Nat Genet. 2010 Dec;42(12):1109-12 PMID: 21076407
  24. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome.
    Nat Genet. 2012 Mar 18;44(4):376-8 PMID: 22426308
  25. A landscape of driver mutations in melanoma.
    Cell. 2012 Jul 20;150(2):251-63 PMID: 22817889
  26. BAF200 is required for heart morphogenesis and coronary artery development.
    PLoS One. 2014 Oct 09;9(10):e109493 PMID: 25299188
  27. Essential role of ARID2 protein-containing SWI/SNF complex in tissue-specific gene expression.
    J Biol Chem. 2012 Feb 10;287(7):5033-41 PMID: 22184115
  28. PBAF chromatin-remodeling complex requires a novel specificity subunit, BAF200, to regulate expression of selective interferon-responsive genes.
    Genes Dev. 2005 Jul 15;19(14):1662-7 PMID: 15985610
  29. Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability.
    Am J Hum Genet. 2012 Mar 9;90(3):565-72 PMID: 22405089
  30. SRF-dependent gene expression is required for PI3-kinase-regulated cell proliferation.
    EMBO J. 2000 Sep 15;19(18):4955-66 PMID: 10990459
  31. Transcription regulation and animal diversity.
    Nature. 2003 Jul 10;424(6945):147-51 PMID: 12853946
  32. Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression.
    Nature. 2004 Mar 11;428(6979):185-9 PMID: 15014501
  33. A framework for variation discovery and genotyping using next-generation DNA sequencing data.
    Nat Genet. 2011 May;43(5):491-8 PMID: 21478889
  34. The role of BAF (mSWI/SNF) complexes in mammalian neural development.
    Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):333-49 PMID: 25195934
  35. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.
    Nat Genet. 2012 May 06;44(6):694-8 PMID: 22561517
  36. ARID proteins come in from the desert.
    Trends Biochem Sci. 2000 Jun;25(6):294-9 PMID: 10838570
  37. Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome.
    Nat Genet. 2012 Feb 26;44(4):445-9, S1 PMID: 22366787
  38. A new paradigm emerges from the study of de novo mutations in the context of neurodevelopmental disease.
    Mol Psychiatry. 2013 Feb;18(2):141-53 PMID: 22641181
  39. Genetic heterogeneity in Rubinstein-Taybi syndrome: delineation of the phenotype of the first patients carrying mutations in EP300.
    J Med Genet. 2007 May;44(5):327-33 PMID: 17220215
  40. A balanced translocation t(6;14)(q25.3;q13.2) leading to reciprocal fusion transcripts in a patient with intellectual disability and agenesis of corpus callosum.
    Cytogenet Genome Res. 2011;132(3):135-43 PMID: 21042007
  41. Clonal architectures and driver mutations in metastatic melanomas.
    PLoS One. 2014 Nov 13;9(11):e111153 PMID: 25393105
  42. ATP-dependent chromatin remodeling in neural development.
    Curr Opin Neurobiol. 2009 Apr;19(2):120-6 PMID: 19442513
  43. Differential targeting of two distinct SWI/SNF-related Drosophila chromatin-remodeling complexes.
    Mol Cell Biol. 2004 Apr;24(8):3077-88 PMID: 15060132
  44. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome.
    Nat Genet. 2004 Sep;36(9):955-7 PMID: 15300250
  45. Fast and accurate short read alignment with Burrows-Wheeler transform.
    Bioinformatics. 2009 Jul 15;25(14):1754-60 PMID: 19451168
  46. Loss of function of SWI/SNF chromatin remodeling genes leads to genome instability of human lung cancer.
    Oncol Rep. 2015 Jan;33(1):283-91 PMID: 25370573
  47. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
    Nature. 2012 Apr 04;485(7397):246-50 PMID: 22495309
  48. ATP-dependent chromatin-remodeling complexes.
    Mol Cell Biol. 2000 Mar;20(6):1899-910 PMID: 10688638
  49. Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B.
    Clin Genet. 2012 Sep;82(3):248-55 PMID: 21801163
  50. Swi/Snf chromatin remodeling/tumor suppressor complex establishes nucleosome occupancy at target promoters.
    Proc Natl Acad Sci U S A. 2013 Jun 18;110(25):10165-70 PMID: 23723349
  51. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome.
    Nat Genet. 2012 Mar 18;44(4):379-80 PMID: 22426309
  52. Vulnerabilities of mutant SWI/SNF complexes in cancer.
    Cancer Cell. 2014 Sep 8;26(3):309-17 PMID: 25203320
Article Info
Journal
Neurogenetics
Abbr.
Neurogenetics
ISSN
1364-6753
DOI
10.1007/s10048-015-0454-0
Email
wkc15@columbia.edu
Published
2015-10-00
Epub
2015-00-04
Pages
307-14
Language
English
Region
United States
NLM ID
9709714
Subset
IM
External Links
PubMed source DOI: 10.1007/s10048-015-0454-0 View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2